Hokusai-VTE: Edoxaban Safety Impresses

Action Points

Edoxaban, an oral factor Xa inhibitor, had similar efficacy as warfarin but superior safety in patients with venous thromboembolism (VTE).

Point out that edoxaban was associated with significantly less bleeding in a broad spectrum of patients with venous thromboembolism compared with standard therapy.

Edoxaban, an oral factor Xa inhibitor, had similar efficacy as warfarin but superior safety in patients with venous thromboembolism (VTE), the Hokusai-VTE trial found.

The randomized, double-blind trial of more than 8,000 patients found a 3.2% primary efficacy outcome of recurrent symptomatic VTE with edoxaban versus 3.5% for warfarin (HR 0.89, 95% CI 0.70-1.13, P<0.001 for noninferiority), according to Harry Buller, MD, PhD, of the University of Amsterdam, and colleagues.

But significantly fewer people on the study drug reached the safety endpoint of major or clinically relevant nonmajor bleeding -- 8.5% versus 10.3% (HR 0.81, 95% CI 0.71-0.94, P=0.004 for superiority), they reported in the study published online in the New England Journal of Medicine.

"Physicians that want to give patients low-molecular weight heparin for a few days now have the possibility of following that up with edoxaban," Buller told MedPage Today during an interview.

The study was also presented at the European Society of Cardiology meeting in Amsterdam.

Buller highlighted the drug's efficacy in a high-risk subgroup (35% of the total) with pulmonary embolism (PE) who had right ventricular dysfunction as determined by elevated N-terminal pro-brain natriuretic peptide levels. In this group, 3.3% of those on edoxaban had recurrent VTE compared with 6.2% of the warfarin group (HR 0.52, 95% CI 0.28-0.98).

Typically, those with severe PE are under-represented in similar trials, such as EINSTEIN-VTE and AMPLYFY-EXT, Buller said. He suggested that physicians felt more comfortable enrolling riskier patients in Hokusai-VTE because patients initially received low-molecular weight heparin.

As good as the results are for edoxaban, both rivaroxaban and apixaban showed slightly better efficacy and safety results.

All patients in the Hokusai-VTE trial received initial therapy with open-label enoxaparin or unfractionated heparin for at least 5 days. The median duration of heparin therapy after randomization was 7 days.

In Hokusai-VTE, researchers compared outcomes in patients receiving heparin followed by edoxaban (60 mg once daily) with heparin followed by warfarin.

Three patient populations, however, received 30 mg once daily: those with renal impairment, those who weighed less than 132 lbs, and those receiving concomitant treatment with potent P-glycoprotein inhibitors.

This group, which comprised about one-fifth of the total population, "maintained efficacy with significantly less bleeding than that observed in the warfarin group."

The protocol called for patients to continue treatment on their anticoagulant for at least 3 months and for up to a year. Forty percent of patients continued the study drug for 12 months. The treating physician determined the duration.

Total enrollment was 8,292 patients from 439 centers in 37 countries. The overall mean age was 55, which was also the mean age of patients with only deep vein thrombosis (DVT). Those with PE were slightly older (mean 57).

Overall, 57% were men, increasing to 60% for those only with DVT and dropping to 52% for those with PE.

The investigators noted that the overall time in the therapeutic range for warfarin patients was 63.5%, "which is a higher percentage of time in the therapeutic range than the 40% to 50% seen in registries of clinical practice."

They also said the findings are "likely generalizable" because they included "patients with both provoked and unprovoked VTE" with variable treatment durations.

Buller pointed out that future studies will focus on the use of edoxaban alone in "ideal" low-risk patients. "But at the other end of the spectrum, you better start with low-molecular weight heparin."

A coordinating committee in collaboration with the sponsor (Daiichi Sankyo) was responsible for the design and oversight of the study and for developing the protocol.

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